Traumatic brain injury (TBI) results in cognitive and motor deficits involving altered excitatory neurotransmission and plasticity, including a loss of long term potentiation (LTP). Abnormal excitatory synaptic function could result from changes in network circuitry, synapse number or morphology, and/or presynaptic or postsynaptic neuronal function. The overall objective of our research is to understand the mechanisms involved in TBI-induced alterations of excitatory transmission at the electrophysiological, biochemical and molecular level. Our hypothesis is that TBI-induced changes in the properties and/or regulation of postsynaptic glutamate receptors contribute to the alterations in synaptic function and information processing observed in surviving neurons after TBI. In vitro traumatic injury produces highly novel changes in neuronal glutamate receptors, which mediate excitatory synaptic transmission and plasticity. Patch clamp electrophysiology, confocal microscopy, immunocytochemistry, and Western blot analysis will be used to study cultured cortical and hippocampal pyramidal neurons sub lethally injured using the in vitro stretch model. We will determine whether injury-induced changes in excitatory postsynaptic currents are due to direct alterations in postsynaptic AMPA and NMDA receptors and identify the specific intracellular signaling systems involved, which we hypothesize may include calcium/calmodulin kinase II, and PKC. Furthermore, we will determine whether activation of these intracellular pathways following injury leads to abnormal glutamate receptor phosphorylation during basal synaptic transmission and under conditions that normally induce synaptic plasticity. Carrying out these Specific Aims will elucidate how mechanical injury alters excitatory synaptic transmission and synaptic regulation in both the cortex and hippocampus and determine if these alterations are mediated by changes in postsynaptic glutamate receptors, including abnormal receptor phosphorylation. An understanding of the molecular mechanisms responsible for abnormal synaptic transmission in specific brain regions following TBI may assist in the development of new TBI treatments and will help direct future research of cognitive and motor deficits following in vivo TBI.